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Effect of caffeine and cannabidiol (CBD) co-administration on Δ9-tetrahydrocannabinol (Δ9-THC) subjective effects, performance impairment, and pharmacokinetics.

Justin C Strickland, Hayleigh E Tilton, Noah M Patton, Ryan Vandrey, C Austin Zamarripa, Tory R Spindle, Dustin C Lee, Cecilia L Bergeria, David Wolinsky, Jost Klawitter, Cristina Sempio, Jorge Campos-Palomino, Uwe Christians, Matthew T Feldner, Jessica G Irons, Marcel O Bonn-Miller

Neuropsychopharmacology November 1, 2025 DOI: 10.1038/s41386-025-02232-x (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Double-blind, randomized, placebo-controlled, within-subject crossover study Peer reviewed
Sample size 20
Population Healthy adults (10 men, 10 women)
Interventions Δ9-THC caffeine CBD
Dose 7.5 mg cumulative Δ9-THC, 180 mg cumulative caffeine, 105 mg cumulative CBD
Duration Outpatient laboratory sessions
Topics Cannabis CBD
Key points Caffeine produced minimal changes in THC-induced effects, but CBD increased outcomes associated with abuse liability and performance impairment, and increased plasma THC and 11-OH-THC concentrations.

Abstract

Cannabis products premixed with caffeine are increasingly present in the United States marketplace. Despite emergence of this product class, no human laboratory data have directly evaluated the isolated impact of caffeine on Δ9-tetrahydrocannabinol (Δ9-THC) effects as well as additional impacts of other common co-administered cannabinoids. This double-blind, randomized, placebo-controlled, within-subject crossover study evaluated potential pharmacodynamic and pharmacokinetic interactions between/among Δ9-THC, caffeine, and cannabidiol (CBD). Participants (N = 20; 10 men/10 women) completed outpatient laboratory sessions in which oral Δ9-THC (7.5 mg cumulative), caffeine (180 mg cumulative), and/or CBD (105 mg cumulative) were co-administered in a cumulative dosing design. Primary outcomes included subjective effects indicative of abuse liability (e.g., drug high), performance effects that underlie safety risk (e.g., simulated driving), and plasma cannabinoid/caffeine concentrations. Caffeine co-administration produced minimal changes in Δ9-THC-induced subjective effects, performance, or metabolism, although signals for perceived driving impairment were observed. In contrast, CBD, when co-administered with Δ9-THC and caffeine increased outcomes associated with abuse liability (e.g., drug high, p = 0.002) and performance impairment versus Δ9-THC alone. CBD also increased plasma Δ9-THC (p = 0.004) and 11-OH-Δ9-THC (p < 0.001) concentrations compared with dose conditions without CBD co-administration. These data provide the first direct assessment of the pharmacodynamic and pharmacokinetic effects of Δ9-THC and caffeine when co-administered in humans. The robust alteration of Δ9-THC-induced effects and Δ9-THC pharmacokinetics by CBD further emphasizes the importance of considering full cannabinoid profiles. Broadly, these data highlight the importance of considering drug combinations and interactions in future cannabis regulatory decision-making.

Comparable studies

Other randomized controlled trials on CBD, most cited first.

Study Year Design Participants
Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment Healthy participants 2012 Randomized controlled trial n = 48
Distinct Effects of Δ9-Tetrahydrocannabinol and Cannabidiol on Neural Activation During Emotional Processing Healthy, English-native, right-handed men who had used cannabis 15 times or less in... 2009 Double-blind, randomized, placebo-controlled crossover trial n = 15
Inverted U-Shaped Dose-Response Curve of the Anxiolytic Effect of Cannabidiol during Public Speaking in Real Life Healthy subjects aged 18 to 35 years 2017 Randomized controlled trial n = 60
Acute Effects of a Single, Oral dose of d9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) Administration in Healthy Volunteers Healthy male subjects 2012 Randomized controlled trial n = 16
Modulation of Mediotemporal and Ventrostriatal Function in Humans by Δ9-Tetrahydrocannabinol Healthy, native English-speaking, right-handed men of white race/ethnicity who had used... 2009 Randomized controlled trial n = 15

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